Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup

  • Bioorg Med Chem Lett. 2015 Jul 15;25(14):2793-9. doi: 10.1016/j.bmcl.2015.05.008.
Pratik Devasthale  1 ,  Wei Wang  2 ,  Andres S Hernandez  2 ,  Fang Moore  2 ,  Kishore Renduchintala  3 ,  Radhakrishnan Sridhar  3 ,  Mary Ann Pelleymounter  4 ,  Daniel Longhi  4 ,  Ning Huang  4 ,  Neil Flynn  4 ,  Anthony V Azzara  4 ,  Kenneth Rohrbach  4 ,  James Devenny  4 ,  Suzanne Rooney  4 ,  Michael Thomas  4 ,  Susan Glick  4 ,  Helen Godonis  4 ,  Susan Harvey  4 ,  Mary Jane Cullen  4 ,  Hongwei Zhang  5 ,  Christian Caporuscio  5 ,  Paul Stetsko  5 ,  Mary Grubb  5 ,  Christine Huang  5 ,  Lisa Zhang  5 ,  Chris Freeden  5 ,  Yi-Xin Li  5 ,  Brian J Murphy  4 ,  Jeffrey A Robl  2 ,  William N Washburn  2
Affiliations
  • 1. Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States. Electronic address: [email protected].
  • 2. Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
  • 3. BMS-Biocon Research Center, Biocon, 20th KM, Hosur Road, Electronic City, Bangalore 560 100, India.
  • 4. Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
  • 5. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
PMID: 26022839 DOI: 10.1016/j.bmcl.2015.05.008
Abstract

Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.

Keywords
Dihydropyrrolopyrazolones; MCHR1 receptor antagonists; Obesity; Off-rates.